Substituted aryloxy-3,3,3-trifluoro-2-propionic acids, esters and salts thereof

ABSTRACT

Derivatives of 2-hydroxy-3,3,3-trifluoro-2-(alkyl or trifluoromethyl)propionic acid bearing a phenyl or naphthyl group linked to the 2-hydroxy group either directly or via an intermediate methylene group. The compounds reduce the concentrations of cholesterol, total esterified fatty acids or fibrinogen in the blood plasma of test animals and some compounds show anti-arthritic properties.

This invention relates to fluorinated compounds and in particular itrelates to fluorinated compounds which have a desirable influence on atleast one of the factors involved in atherosclerotic disease. Inaddition, some of the fluorinated compounds shown anti-arthriticproperties.

According to the invention there is provided a fluorinated compound ofthe formula: ##STR1## wherein Ar is a phenyl or naphthyl radical whichmay optionally bear as substituent a halogen atom or an alkyl or alkoxyradical of 1-4 carbon atoms, or a phenyl or phenoxy radical which mayitself bear as substituent a halogen atom or an alkyl or alkoxy radicalof 1-4 carbon atoms; X is a group of the formula --O.CH₂ -- or --CH₂ --or a direct link between the group Ar and the adjacent oxygen atom; R¹is a hydroxy, amino or dimethylamino radical, or an alkoxy radical of1-6 carbon atoms optionally substituted by a carbamoyl radical or anN,N-dialkylcarbamoyl or dialkylamino radical in which the alkyl radicalsare of 1-6 carbon atoms, a pyridyl radical, a halophenoxy radical or agroup of the formula Ar.X.O.C(CF₃)R².CO.O--; and R² is a hydrogen atomor an alkyl radical of 1-4 carbon atoms or a trifluoromethyl radical;or, for a compound wherein R¹ is a hydroxy radical, a pharmaceuticallyacceptable base addition salt thereof.

It will be observed that those compounds of formula I wherein R² isother than a trifluoromethyl radical contain an asymmetric carbon atomand that accordingly, such compounds can be isolated in a racemic formand two optically active forms. This specification is addressed to theracemic form of the compounds of formula I wherein R² is other than atrifluoromethyl radical and any optical isomer which shows the aboveuseful properties; it being a matter of general knowledge how to resolvethe racemic form and how to determine the biological properties of theoptical isomers.

A particularly suitable value for a substituent which may be present onthe phenyl or naphthyl radical Ar is, for example a fluorine, chlorine,bromine or iodine atom, a methyl or methoxy radical or a phenyl orphenoxy radical optionally bearing a fluorine, chlorine, bromine oriodine atom or a methyl or methoxy radical. Specific values for Ar are,for example, a phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl,4-biphenylyl, 4-phenoxyphenyl, 4-(4-chlorophenyl)phenyl, 1-naphthyl,2-naphthyl, 4-chloro-1-naphthyl, 2-methyl-1-naphthyl,6-chloro-2-naphthyl or 6-methoxy-2-naphthyl radical.

A particularly suitable value for R¹ when it is an alkoxy radical of 1-6carbon atoms is, for example, a methoxy, ethoxy, propoxy or butoxyradical, and a particularly suitable value for a substituent which maybe present on an alkoxy radical when it is a value for R¹ is, forexample, a carbamoyl, N,N-dimethylcarbamoyl, dimethylamino,diethylamino, 3-pyridyl or a 4-chlorophenoxy radical. Specific valuesfor R¹ when it is a substituted alkoxy radical are, for example, a3-(N,N-dimethylcarbamoyl)propoxy, 2-(diethylamino)ethoxy,3-pyridylmethoxy or 2-(4-chlorophenoxy)-2-methylpropoxy radical, or thegroup Ar.X.O.C(CF₃)R² .CO.O.(CH₂)₃ O--, i.e. the group forming a diesterwith 1,3-propanediol.

A particularly suitable value for R² when it is an alkyl radical of 1-4carbon atoms is, for example, a methyl radical.

Particularly suitable base addition salts of a compound wherein R¹ is ahydroxy radical are, for example, alkali metal and alkaline earth metalsalts, for example sodium, potassium, calcium or magnesium salts,aluminium salts, for example an aluminium hydroxide di-salt, or saltswith organic bases, for example ethyl nictotinate, ethyl5-fluoronicotinate, nicotinyl alcohol, 2-aminoethyl nicotinate or2-diethylaminoethyl nicotinate.

A particular group of compounds of formula I comprises those compoundswherein X is a methylene (--CH₂ --) group and R² is a trifluoromethylradical. Preferred among these compounds are those wherein Ar is aphenyl radical optionally substituted by a halogen atom or a halophenylradical, or Ar is a naphthyl radical optionally substituted by a halogenatom or an alkyl or alkoxy radical of 1-4 carbon atoms.

A second particular group of compounds of formula I comprises thosecompounds wherein X is a direct link and R² is a trifluoromethylradical. Preferred among these compounds are those wherein Ar is aphenyl radical optionally substituted by a halogen atom, an alkyl oralkoxy radical of 1-4 carbon atoms, or a phenyl, phenoxy or halophenylradical, or Ar is a naphthyl radical.

A third particular group of compounds of formula I comprises thosecompounds wherein X is a direct link and R² is a methyl radical.Preferred among these compounds are those wherein Ar is a phenyl radicaloptionally substituted by a halogen atom, or a phenyl, phenoxy orhalophenyl radical.

A fourth particular group of compounds of formula I comprises thosecompounds wherein X is a methylene (--CH₂ --) group and R² is a methylradical. Preferred among these compounds are those wherein Ar is aphenyl radical optionally substituted by a halogen atom or a halophenylradical, or Ar is a naphthyl radical optionally substituted by a halogenatom or an alkyl or alkoxy radical of 1-4 carbon atoms. Particularlypreferred are those compounds wherein Ar is a phenyl radical substitutedby a halophenyl radical, for example a 4-chlorophenyl radical, or Ar isa naphthyl radical optionally substituted by a halogen atom, for examplea chlorine atom.

In each of the above groups, R¹ may be as stated above, but preferredvalues for R¹ are a hydroxy or amino radical or an alkoxy radical of 1-6carbon atoms, for example a methoxy or ethoxy radical.

Specific compounds of formula I are set out in the Examples, and ofthese, the following compounds are preferred:

2-[4-(4-chlorphenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid,

2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid,

2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methyl-propionic acid,

2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methyl-propionic acid,

2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid

2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoro-methylpropionic acid.

The compounds of formula I may be made by processes which are applicableto the manufacture of analogous compounds. Such processes areexemplified by the following in which Ar, X, R¹ and R² have the meaningsstated above:

a. Reacting a compound of the formula:

    Ar.X.Z                                                     II

wherein when X is other than a direct link, Z is a halogen atom or analkane- or arene- sulphonyloxy group, for example a chlorine or bromineatom or a methanesulphonyloxy or toluene-p-sulphonyloxy group, and whenX is a direct link, Z is an aryliodonium or 2-thienyliodonium radical,with a salt of the formula: ##STR2## wherein M⁺ is a metal cation, and apreferred value for R¹ is an amino or dimethylamino radical, or analkoxy radical optionally substituted as stated above.

The salt of formula III may be pre-formed from a hydroxy compound offormula IV and a base, which is preferred, or it may be formed in thereaction by using the hydroxy compound of the formula: ##STR3## asstarting material and carrying out the reaction in the presence of abase. A convenient value for M is an alkali metal, for example sodium orpotassium, and a convenient base is, for example, sodium or potassiumhydride.

When X is other than a direct link, the reaction is conveniently carriedout at ambient temperature for an extended period in an inert solvent,for example dimethylformamide, and when X is a direct link, the reactionis conveniently carried out by heating a salt of the cation of theformula: ##STR4## for example a chloride, bromide, acetate, hydrogensulphate or trifluoroacetate, with an alkali metal salt of formula IIIeither in the absence of a solvent or in an inert high boiling solvent,for example xylene or toluene, or initially in the absence of a solventand subsequently in the presence of a solvent.

b. For a compound of formula I wherein R¹ is a hydroxy radical,hydrolysing an ester of the formula: ##STR5## wherein R³ is an alkoxyradical of 1-6 carbon atoms.

The hydrolysis is conveniently carried out, for example, by reacting theester of formula V with a base, for example sodium hydroxide orpotassium hydroxide, in an inert solvent, for example ethanol ormethanol optionally mixed with water. R³ is preferably a methoxy orethoxy radical, and the hydrolysis is conveniently carried out at roomtemperature for a period of 11/2 hours to 3 days. A short hydrolysistime, for example 2-5 hours, is effective in many cases, but a longertime may often be employed.

c. For a compound of formula I wherein R¹ is an amino radical,hydrolysing a nitrile of the formula: ##STR6##

The hydrolysis is conveniently carried out, for example, by reacting thenitrile of formula VI with a base, for example sodium hydroxide orpotassium hydroxide, in an inert solvent, for example methanol orethanol optionally mixed with water. The hydrolysis is convenientlycarried out at room temperature for a period of several days, or ashorter period at 60°-80° C.

d. For a compound of formula I wherein R¹ is an amino or dimethylaminoradical, reacting ammonia or dimethylamine with an acid halide of theformula: ##STR7## wherein Hal stands for a halogen atom, preferably achlorine or bromine atom.

The reaction is conveniently carried out by reacting aqueous ammonia oraqueous dimethylamine with the acid halide at ambient temperature, butother solvents may be employed and the reaction mixture may be heated.

e. For a compound of formula I wherein R¹ is an alkoxy radial optionallysubstituted as defined above, esterifying the corresponding acid offormula I wherein R¹ is a hydroxy radical.

The esterification may be conveniently carried out using thecorresponding diazoalkane, particularly when R¹ is a methoxy radical; byreacting the acid with the alcohol in the presence of an acid catalyst;or by reacting an acid halide, especially an acid chloride or bromide,or anhydride with the alcohol in the presence of a base, for examplepyridine, triethylamine or N,N-dimethylaniline.

f. For a compound wherein R¹ is a dimethylamino radical and R² ishydrogen, heating a compound of the formula: ##STR8## withdimethylformamide and sodium hydride.

The heating is conveniently carried out at 100° C. for 12-24 hours.

When an optical isomer of a compound of formula I, wherein R² is otherthan a trifluoromethyl radical, is desired, the corresponding racemiccompound may be resolved or one of the above processes may be carriedout using an optically active starting material. For example an acid offormula I wherein R¹ is a hydroxy radical may be resolved by fractionalcrystallization of a salt formed with an optically active base, forexample (+)- or (-)-ephedrine, from a solvent, for example toluene. Theoptically active acid may then be recovered from the salt in the usualway and esterified to give an optically active ester.

As indicated above, the compounds of the invention are able to exert adesirable influence on one or more of the factors involved inatherosclerotic disease. These factors are elevated concentrations ofcholesterol, total esterified fatty acids and fibrinogen in the bloodplasma, and the compounds of the invention are capable of lowering theconcentration of at least one member of the above group of blood plasmacomponents in warm blooded animals. This property is demonstrated instandard tests by the effect of the compounds in lowering theconcentration of the relevant blood plasma component to at least 80% ofthe control value when administered orally to rats over a period of 7 to14 days, or by their activity, or that of the corresponding acid, invitro, in displacing thyroxine from human albumin when present in anequimolar amount relative to the albumin. In this test an increase inthe amount of unbound thyroxine similar to that produced by2-(4-chlorophenoxy)-2-methylpropionic acid is considered to representhighly significant activity. In these tests, no overt toxic effects werenoticed at the active dose.

When used to lower the concentrations of the above blood plasmacomponents in warm blooded animals, the compounds may be administered inthe diet at concentrations from 0.005% to 0.2%, or they may beadministered orally in the form of a pharmaceutical composition so thata daily dose of from 5 mg./kg. to 200 mg./kg. is received by the host.In man this is equivalent to a dose of 0.1 g. to 2 g. per day given individed doses.

The anti-arthritic properties of some of the compounds of formula I aredemonstrated by their effect in inhibiting the increase in the thicknessof a rat's foot injected with dead tubercle bacilli when administeredover 21 days, essentially according to the standard test of Newbould(Brit. J. Pharmacol., 1963, 21, 127-136), and also their effect ininhibiting the increase in the concentration of α₁ acid glycoprotein inthe blood serum of the rats used in this test. Compounds of formula Iwherein X is a methylene (--CH₂ --) group or a direct link, R² is amethyl or trifluoromethyl radical and Ar is a phenyl radical substitutedin the 4-position by a halophenyl radical, particularly a 4-chlorophenylradical, or Ar is a naphthyl radical substituted by a halogen atom,particularly a chlorine atom, show activity without overt toxic effectsat a daily dose of 50 mg./kg. or less. The preferred compound is2-[4-(4-chlorophenyl)benzyl-oxy]-3,3,3-trifluoro-2-methylpropionic acidor a salt thereof.

When used to produce anti-arthritic effects in warm blooded animals,those of the compounds of formula I defined immediately above may beadministered orally at a daily dose of from 1 to 100 mg./kg. In man thisis equivalent to a total daily dose of from 25 to 1000 mg. given, ifnecessary, in divided doses.

The compounds of the invention may be administered in the form ofpharmaceutical compositions and according to a further feature of theinvention there is provided a pharmaceutical composition which comprisesa fluorinated compound of the invention in pharmaceutically acceptableform.

By "pharmaceutically acceptable form" is meant either a pharmaceuticalpreparation in which the compound is associated with a pharmaceuticallyacceptable diluent, or a pharmaceutical preparation, for example acapsule, in which the compound is confined in a unit dosage form withoutnecessarily being associated with a diluent.

Preferred pharmaceutically acceptable forms are those suitable for oraladministration, for example tablets, capsules, suspensions or solutions,which may be obtained by conventional methods and, if desired, by usingconventional diluents or excipients. Dosage forms should contain from 50mg. to 500 mg. of fluorinated compound per dosage unit.

Compositions intended for use in the treatment of atheroscleroticdisease may also contain other agents which can have a beneficial effecton the disease or associated conditions, for example nicotinyl alcohol,nicotinic acid or a salt thereof, raubasine, vitamin E, an anionexchange resin, for example cholestyramine, colestipol or adialkylaminoalkyl derivative of a crosslinked dextran, or a calcium ormagnesium salt, or metformin or phenformin.

Compositions intended for use in the treatment of arthritis may alsocontain other agents having antiinflammatory or analgesic activity, forexample, aspirin, paracetamol, codeine, chloroquine, phenylbutazone,D-penicillamine, indomethacin, ibuprofen, ketoprofen or naproxen, or ananti-inflammatory steroid, for example prednisolone, or a uricosuricagent, for example probenecid.

The invention is illustrated but not limited by the following Examples:-

EXAMPLE 1

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) isadded dropwise at ambient temperature to a stirred mixture of sodiumhydride (2.4 g. of a 60% dispersion in oil) and dimethylformamide (100ml.). The mixture is stirred for 4 hours, 4-chlorobenzyl chloride (8.4g.) is added, and the stirring is continued for 6 days. The mixture isfiltered, and the filtrate is evaporated in vacuo. The residue isfractionally distilled at 0.1 mm. pressure, collecting the fraction,(9.9 g.) b.p. 78°-80° C., m.p. 32°-33° C, which is crystallized frompentane to give ethyl2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, m.p.33° C.

The ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate used asstarting material may be obtained as follows:-

A mixture of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrilesodium salt (200 g.) and concentrated sulphuric acid (500 ml.) is heatedunder reflux for 6 hours. The mixture is distilled at ambient pressureand the fraction (180 g.) which sublimes and distills at 150°-160° C. iscollected. It consists of2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid, pure enoughfor use, but which may be further purified by crystallization from amixture of toluene and light petroleum (b.p. 60°-80° C.), forminghygroscopic crystals m.p. 76°-82° C.

A mixture of the above carboxylic acid (106 g.), anhydrous ethanol (100ml.) and concentrated sulphuric acid (20 ml.) is heated under reflux for75 hours, cooled, and poured into a mixture of ice and water (1.5 l.).The oily organic phase is separated, the aqueous phase is extracted withlight petroleum (b.p. 40°-60° C.), and the combined oil and extract isdried by filtration through phase-separating paper, then evaporated. Theresidue is fractionally distilled at ambient pressure. After a forerun,which is discarded, the ethyl2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (72.2 g.), b.p.119°-121° C., is collected.

EXAMPLE 2

A mixture of ethyl2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (3.65g.), N-aqueous sodium hydroxide (100 ml.) and ethanol (50 ml.) isstirred at ambient temperature for 2 days, and then evaporated in vacuo.Water is added, and the mixture is washed with ether. The aqueous phaseis acidified with concentrated hydrochloric acid and extracted withether. The extract is dried with sodium sulphate, evaporated, and theresidue is crystallised from light petroleum (b.p. 40°-60° C.) to give2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid,m.p. 98°-99° C. (1.42 g.).

EXAMPLE 3

A mixture of2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile (20g.), potassium hydroxide (25 g.), ethanol (250 ml.) and water (250 ml.)is heated under reflux for 15 minutes. Most of the ethanol is evaporatedin vacuo, and the residue is cooled until the precipitated oilsolidifies. The solid is filtered off, and is recrystallised from amixture of ether and light petroleum (b.p. 40°-60° C.) (charcoal) togive2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionamide,m.p. 94°-95° C. (13.9 g.).

The 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrileused as starting material may be obtained as follows:-

A mixture of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrilesodium salt (43 g.), 4-chlorobenzyl chloride (25.6 g.) anddimethylformamide (200 ml.) is stirred at ambient temperature for 5days, then evaporated in vacuo. Water is added to the residue, and themixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane. Theextract is dried with sodium sulphate, and evaporated. The residue isdistilled to give2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile,b.p. 54°-64° C. at 1 mm. pressure (41.0 g.).

EXAMPLE 4

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (54.6 g.) isadded dropwise, under nitrogen, at 0° C. during 30 minutes to a stirredmixture of sodium hydride (9.6 g. of 60% oil dispersion from which theoil has been washed with light petroleum) and dimethylformamide (500ml.). The mixture is stirred at ambient temperature for 1 hour, and then4-(4-chlorophenyl)benzyl chloride (43.1 g.) is then added in one lot.The resulting solution is stirred under nitrogen for 120 hours at30°-35° C., then evaporated in vacuo. The residue is mixed with water,and the mixture is extracted with ether. The ethereal extract is washedwith water, dried with sodium sulphate and evaporated. The residue isdigested with boiling light petroleum (b.p. 40°-60° C.), the insolublematerial is filtered off, and the filtrate is treated with charcoal,filtered, concentrated and cooled. Crops of crystals (42.3 g.) meltingin the range 57°-62.5° C. are collected and recrystallised to give ethyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate,(39.9 g.) m.p. 62°-62.5° C.

The above general procedure is repeated but the 4-(4-chlorophenyl)benzylchloride is replaced by molar equivalent quantities of:-

a. 1-chloromethylnaphthalene

b. 1-chloromethyl-4-chloronaphthalene

c. 2-chloromethylnaphthalene

d. 1-chloromethyl-2-methylnaphthalene

e. 2-chloromethyl-6-chloronaphthalene

to give (a) ethyl2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, (b)ethyl2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionateand (c) ethyl2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionaterespectively as oils, and (d) ethyl2-(2-methyl-1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate,m.p 53°-54.5° C., (50 g.) and (e) ethyl2-(6-chloro-2-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate,m.p. 64°-65° C., after chromatography in light petroleum (b.p. 40°-60°C.) on a column of neutral grade I alumina using a mixture of lightpetroleum (b.p. 40°-60° C.) and ether (19:2) as eluant, andrecrystallisation from light petroleum (b.p. 40°-60° C.).

The 2-chloromethyl-6-chloronaphthalene used as starting material may beobtained as follows:-

1.9N-Aqueous sodium hypochlorite solution (924 ml.) is added, dropwiseat 50°-60° C. to a stirred suspension of 2-acetyl-6-chloronaphthalene(53.2 g.) in ethanol (420 ml.) during 1 hour. The stirring is continuedfor 1 hour. The mixture is cooled and treated, dropwise at 38° C., with40% aqueous sodium hydrogen sulphite solution (ca. 50 ml.) until nounreacted hypochlorite remains, and is then acidified with concentratedhydrochloric acid below 25° C. 6-Chloro-2-naphthoic acid (42 g.) m.p.279°-286° C. is precipitated and is collected, and may be furtherpurified by recrystallisation from toluene to give material of m.p.286°-287° C.

A suspension of the 6-chloro-2-naphthoic acid (41.2 g.) in a mixture ofmethanol (500 ml.) and concentrated sulphuric acid (50 ml.) is heatedunder reflux for 3 hours, stored at ambient temperature for 3 days, thenwarmed until a solution is obtained. Water (2 l.) and ether (1 l.) areadded. The ethereal layer is separated, and is washed in turn withwater, N-aqueous sodium hydroxide, and water, dried with magnesiumsulphate, and evaporated to give methyl 6-chloro-2-naphthoate (38.8 g.)m.p. 97°-98° C., which may be further purified by recrystallisation fromlight petroleum (b.p. 40°-60° C.) to give material of m.p. 100°-101° C.

A solution of the methyl 6-chloro-2-naphthoate (111 g.) in ether (2.5l.) is added, dropwise below 25° C. under nitrogen, to a stirred mixtureof ether (250 ml.) and a 70% solution (250 ml.) of sodiumdihydro-bis-(2-methoxyethoxy)aluminate in benzene during 1 hour. Themixture is stirred for a further 30 minutes and 2N-hydrochloric acid(250 ml.) is added cautiously. The solution is decanted from undissolvedsolid, and concentrated hydrochloric acid is added to the solid until itdissolves. The two solutions thus obtained are combined, and ether (1l.) and a mixture of ice and water (1 l.) are added. The ethereal layeris separated, and the aqueous phase extracted with ether. The etherealsolutions are combined, washed with water, dried and evaporated to give6-chloro-2-hydroxymethylnaphthalene (95 g.) which may be furtherpurified by crystallisation from toluene to give material of m.p.134°-137° C.

Thionyl chloride (99.4 g.) is added dropwise at 0° C. during 1 hour to astirred suspension of the 6-chloro-2-hydroxymethylnaphthalene (96.3 g.)in a mixture of pyridine (59.0 g.) and chloroform (2 3 l). The mixtureis stirred for 1 hour at 20° C., then treated dropwise with methanol (60ml.) and stored for 18 hours. The solution is washed with water,3N-hydrochloric acid, and water again, dried with magnesium sulphate andevaporated. The residue is crystallised from light petroleum (b.p.80°-100° C.) to give 2-chloromethyl-6-chloronaphthalene (101 g.) m.p.107°-110° C. raised to 110°-111° C. by further crystallisation.

EXAMPLE 5

A mixture of ethyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate(3.3 g.), N aqueous sodium hydroxide (15 ml.) and ethanol (80 ml.) isstirred at ambient temperature for 18 hours, filtered, and the filtrateis evaporated in vacuo. An aqueous suspension of the residual solid isacidified with concentrated hydrochloric acid. The solid is filteredoff, washed with water, dried and crystallised from cyclohexane to give2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 130°-33° C. (2.5 g.)

EXAMPLE 6

The esters a), b) and c) obtained as oils in the second part of Example4 are hydrolysed by stirring 40 g. of ester with a solution of potassiumhydroxide (6.0 g.) in methanol (300 ml.) and water (30 ml.) at ambienttemperature for 17-22 hours. The solution is evaporated in vacuo, theresidue mixed with water, and the mixture is washed with ether. Theaqueous phase is acidified with concentrated hydrochloric acid, and theresulting emulsion is extracted with ether. The extract is washed withwater, dried with sodium sulphate and evaporated. The residue iscrystallised from light petroleum (b.p. 40°-60° C.) to give thefollowing acids:

2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid,m.p. 101° C (14.3 g.)

2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 118°-121° C. or 105°-106° C. (dimorphic) (20 g.)

2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid,m.p. 109-112° C (15 g.).

The esters d) and e) obtained in the second part of Example 4 arehydrolysed in the same way but the reaction is continued for only 11/2hours to give2-(2-methyl-1-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 110° C. (decomp.) and2-(6-chloro-2-naphthylmethoxy)-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 133°-134.5° C. respectively.

EXAMPLE 7

A solution of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrilesodium salt (4.3 g.) and 4-(4-chlorophenyl)-benzyl chloride (4.7 g.) indimethylformamide (25 ml.) is stirred at ambient temperature for 10days, then diluted with water. During this reaction,2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionitrileis formed and is subsequently hydrolysed to the corresponding amide. Themixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane, and theextract is dried with sodium sulphate, then evaporated. The residue iscrystallised from cyclohexane to give2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionamide,m.p. 123°-124° C. (1.6 g.).

EXAMPLE 8

A stirred suspension of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (750 mg.) in water (10 ml.) is treated dropwise at room temperaturewith 0.4 N-aqueous sodium hydroxide solution (4.50 ml.). The resultantmixture is warmed briefly to 35° C., cooled, and filtered. The filtrateis washed with ether, refiltered, then evaporated in vacuo. The solidresidue is dried in vacuo at 100° C. for 12 hours giving sodium2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionatesesquihydrate (0.74 g.) as a solid, which does not melt below 300° C.

EXAMPLE 9

A solution of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (290 mg.) and ethyl nicotinate (106 mg.) in ether (10 ml.) isstored at room temperature for 18 hours, then evaporated. This residualsolid is dissolved in a small volume of methylene chloride, and thesolution diluted with ether to give the ethyl nicotinate salt of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (301 mg.) m.p. 90°-92° C.

EXAMPLE 10

A solution of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (1.2 g.) in either (20 ml.) is treated at 0° C. with an excess ofan ethereal solution of diazomethane. The solution is evaporated, andthe residue is recrystallised from light petroleum (b.p. 40°-60° C.) togive methyl2-[4(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate(1.1 g.), m.p. 61.5°-62.5° C.

EXAMPLE 11

Ice-cold aqueous ammonia solution (d, 0.88; 10 ml.) is added to2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (0.68 g.). The solid product is filtered off, and iscrystallised from cyclohexane to give2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionamide(0.58 g.), m.p. 123°-124° C.

The2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride used as starting material may be obtained as follows:

A mixture of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (3.0 g.), thionyl chloride (3.0 ml.), dimethylformamide (0.16 g.)and benzene (10 ml.) is heated under reflux until the solution becomesturbid (ca. 10 minutes). The mixture is evaporated in vacuo, benzene (10ml.) is added and the evaporation is repeated. Light petroleum (10 ml.,b.p. 40°-60° C.) is added to the residue, and the solution is separatedfrom insoluble oils and evaporated to give2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (3.07 g.), m.p. 30°-35° C.

EXAMPLE 12

A mixture of 2-diethylaminoethanol (814 mg.) and pyridine (10 ml.) isadded at 0° C. to2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (3.07 g.). The mixture is stirred at room temperature until theacid chloride dissolves, and the solution is stored at 0° C. for 2 days.The mixture is filtered and the filtrate evaporated. The residue istriturated with ether and combined with the solid previously filteredoff. The combined solids are crystallised from dioxan-ether to give2-diethylaminoethyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionatehydrochloride (2.2 g.), m.p. 139°-140° C. (decomposition).

The above procedure is repeated using 3-hydroxymethylpyridine in placeof 2-diethylaminoethanol to give 3-pyridylmethyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionatehydrochloride (2.1 g.), m.p. 143°-145° C. (decomposition).

EXAMPLE 13

A solution of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (3.10 g.) in tetrahydrofuran (10 ml.) is added dropwise at 0°C. to a stirred mixture of 4-hydroxy-N,N-dimethylbutyramide (885 mg.),triethylamine (773 mg.) and tetrahydrofuran (15 ml.). The mixture iskept at room temperature for 4 hours with stirring, and for 2 dayswithout stirring, then filtered. The filtrate is evaporated, and theresidue dissolved in ether. The solution is washed with water, 0.4N-aqueous sodium hydroxide, N-hydrochloric acid and water again, driedand evaporated to a syrup (3.3 g.). The syrup is dissolved in toluene(10 ml.) and applied to a column of silica gel (90 g.). The column iswashed with toluene (700 ml.), and then eluted with ether (900 ml.). Theether is evaporated, and the residue is recrystallised from ether-lightpetroleum (b.p. 40°-60° C.) to give 3-dimethylcarbamoylpropyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethyl-propionate(2.1 g.), m.p. 54°-55° C.

EXAMPLE 14

N,N-Dimethylaniline (467 mg.) in tetrahydrofuran (5 ml.) is added at 10°C. to a stirred mixture of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (2.06 g.), 1,3-propanediol (178 mg.), and tetrahydrofuran (10ml.). The resulting solution is heated under reflux for 2.5 hours, thenevaporated in vacuo. The residue is mixed with ether and water, and theethereal phase is separated, washed with water, 2N-hydrochloric acid,0.5N-aqueous sodium hydroxide and water again, dried and evaporated. Theresidue is triturated with light petroleum (b.p. 30°-40° C.), and thesolid recrystallised twice from light petroleum (b.p. 60°-80° C.) togive trimethylenebis{2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate}(0.72 g.), m.p. 93°-94° C.

EXAMPLE 15

A solution of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionylchloride (3.16 g.) in 1,2-dichloroethane (10 ml.) is added, dropwise andbelow 10° C., to a stirred mixture of2-(4-chlorophenyloxy)-2-methylpropanol (1.40 g.), pyridine (4.0 ml.),and 1,2-dichloroethane (10 ml.). The mixture is stirred at ambienttemperature for 20 hours, then mixed with ice-water and chloroform. Theorganic phase is separated, and washed with 3N-hydrochloric acid andwater. 0.4N-Aqueous potassium hydroxide (5 ml.) and ice are added, themixture is shaken, and enough ether is added to cause the resultingemulsion to separate into two layers. The organic layer is washed withwater, dried and evaporated. The residual oil (3.6 g.) ischromatographed in light petroleum (b.p. 60°-80° C.) on a column ofsilica gel (45 g.). The column is washed portionwise the solvent (2 l )until no more material is eluted, and then with a mixture of lightpetroleum and ether (10:1, 200 ml.). This eluate is evaporated to give2-(4-chlorophenyloxy)-2-methylpropyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate(2.6 g.) as a syrup.

EXAMPLE 16

A mixture of (±)-methyl 2-hydroxy-2-trifluoromethylpropionate (17.2 g.)and dimethyl formamide (20 ml.) is added dropwise at 0° C. to a stirredsuspension of sodium hydride (4.2 g. of a 60% dispersion in oil fromwhich the oil has been washed with light petroleum) in dimethylformamide(200 ml.). The mixture is stirred at ambient temperature for 1 hour, andthen 4-(4-chlorophenyl)benzyl chloride (19.0 g.) is added. The stirringis continued for 4 days, and then the mixture is filtered. The filtrateis evaporated in vacuo, water is added, and the resulting mixture isextracted with ether. The extract is dried with sodium sulphate andevaporated. The residue is repeatedly crystallised from methanol andfrom cyclohexane giving an impure fraction (26.4 g.) (A) and prisms (3.1g.) of (±)-methyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate, m.p.83°-85° C.

The above general procedure is repeated except that the4-(4-chlorophenyl)benzyl chloride is replaced by a molar equivalentquantity of 1-chloromethyl-4-chloronaphthalene,2-chloromethyl-6-chloronaphthalene, 2-chloromethylnaphthalene or1-chloromethylnaphthalene to give, respectively (±)-methyl2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate as anoil (18 g.), (±)-methyl2-(6-chloro-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate, m.p.105°-106° C., (±)-methyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate as a solid or (±)-methyl2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate as an oil.

EXAMPLE 17

A mixture of the impure ester fraction from the previous example(fraction A) of (±)-methyl2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (15.7g.), potassium hydroxide (3.0 g.), methanol (300 ml.) and water (30 ml.)is stirred at ambient temperature for 18 hours. The suspension isfiltered, and the filtrate is evaporated. The residue is mixed withwater, and the mixture is washed with ether. The aqueous phase isacidified with concentrated hydrochloric acid then extracted with ether.The extract is dried with sodium sulphate and evaporated. The residue iscrystallised from cyclohexane and from a mixture of toluene and lightpetroleum (b.p. 60°-80° C.) to give(±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid, m.p. 135°-136° C. (5.7 g.). The above process is repeated with(±)-methyl2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionateobtained as an oil in Example 16, to give(±)-2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionicacid, m.p. 120°-121° C. (11.1 g.).

The above process is repeated with (±)-methyl2-(6-chloro-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate,(±)-methyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate or(±)-methyl 2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionateexcept that the reaction is carried out for 41/2, 2 and 21/2 hoursrespectively to give(±)-2-(6-chloro-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionicacid, m.p. 150°-153° C. (from toluene-cyclohexane),(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p.116°-118° C. (from cyclohexane) or(±)-2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p.82°-84° C. (from light petroleum b.p. 60°-80° C.) respectively.

EXAMPLE 18

A solution of(±)-2-(2-nephthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (5.7g.) or (±)-2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid(4.0 g.) in ether (50 ml.) is treated with an excess of etherealdiazomethane at 0° C. The solution is evaporated and the residuerecrystallised to give, respectively, (±)-methyl2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (3.2 g.) m.p.65°-67° C. (from light petroleum b.p. 60°-80° C.) or (±)-methyl2-(1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (4.1 g.), m.p.31°-33° C. (from methanol).

EXAMPLE 19

A mixture of ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate(2.74 g.) and dimethylformamide (2 ml.) is added, dropwise at 0° C.under nitrogen, to a stirred mixture of sodium hydride (0.48 g. of a 60%oil dispersion from which the oil has been washed with light petroleum)and dimethylformamide (25 ml.). The mixture is stirred at ambienttemperature for 30 minutes, and then 4-[4-chlorophenyl]phenoxymethylchloride (2.30 g.) is added. Stirring is continued for 3 days at 26° C.,and the mixture is evaporated in vacuo. The residue is mixed with water,and the mixture is extracted with ether. The extract is washed withwater, dried with sodium sulphate, and evaporated. The residue isdigested with boiling light petroleum (b.p. 40°-60° C.), insolublematerial is filtered off and the filtrate is run through a small column(2 × 1 cm.) of neutral grade I alumina to remove colour. The elutedmaterial is crystallised from light petroleum (b.p. 30°-40° C.) to giveethyl2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate,m.p. 42°-43° C. (3.0 g.). The 4-[4-chlorophenyl]phenoxymethyl chlorideused as starting material may be obtained as follows:

In a 1-liter round-bottomed flask is placed 4-(4-chlorophenyl)phenol(25.5 g.), 4.0 N aqueous sodium hydroxide (39.0 ml.) and water (75 ml.).The mixture is heated to 90°-100° C., and sodium chloromethyl sulphonate(46.5 g.) is added. The mixture is heated rapidly to 160°-170° C. (bathtemperature) while a current of air is passed through the flask. Whenmost of the water has been removed the temperature of the bath is raisedto, and kept at, 220°-225° C., for 90 minutes; the mixture is thencooled. The solid cakes obtained from two identical experiments areground with water (200 ml.) in a mortar. The resulting suspension isheated to 80° C. and allowed to cool slowly, then filtered. The productis washed with water and dried to give sodium4-(4-chlorophenyl)phenoxymethylsulphonate (58.4 g.) as a cream colouredpowder pure enough for use. It may be further purified bycrystallisation from aqueous dimethylsulphoxide and obtained as amicrocrystalline powder not melting at 300° C.

A mixture of the above crude salt (9.6 g.) and phosphorus pentachloride(12.5 g.) contained in a beaker of 250 ml. capacity is stirredcontinuously by means of a glass rod while the mixture is heated rapidlyto 80°-85° C. (bath temperature). After a few minutes at thistemperature a vigorous reaction takes place and soon subsides. Heatingat 80°-85° C. is continued for a further 30 seconds, then the mixture iscooled.

The combined product obtained from six identical experiments is mixedwith ice and water, and the mixture is extracted with ether. The extractis washed with water, and with saturated aqueous sodium chloride, driedwith sodium sulphate and evaporated in vacuo. The residual solid iscrystallised from light petroleum (b.p. 60°-80° C.) to give4-(4-chlorophenyl)phenoxymethyl chloride, m.p. 68°-70° C. (29.5 g.).

EXAMPLE 20

A mixture of ethyl2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate(502 mg.) potassium hydroxide (88 mg.), methanol (4 ml.) and water (1ml.) is stirred at 20° C. for 22 hours, then evaporated in vacuo. Theresidue is dissolved in water, and the solution is acidified with 3N-hydrochloric acid. The solid which separates is filtered off.Crystallisation from a mixture of cyclohexane and light petroleum (b.p.40°-60° C.) gives prisms (204 mg.) of2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 134°-135° C.

EXAMPLE 21

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (24.0 g.) isadded dropwise at 0° C. to a stirred suspension of sodium hydride (4.0g. of a 60% dispersion in oil from which the oil has been washed withlight petroleum) in light petroleum (200 ml., b.p. 40°-60° C.). Themixture is stirred at ambient temperature for 15 minutes anddi-(4-chlorophenyl)iodonium chloride (38.6 g.) is added. The mixture isstirred thoroughly, and the solvent is evaporated in vacuo. The solidresidue is stirred and heated in a bath to 110° C., at which temperaturea vigorous reaction occurs, and then for a further 15 minutes at 120°C., then cooled. Light petroleum (b.p. 40°-60° C.) is added, insolublematerial is filtered off, and the filtrate is evaporated yielding an oil(53.4 g.).

The crude oil (75.6 g.) obtained from two experiments is chromatographedon a column of silica gel (400 g.) made up in light petroleum (b.p.40°-60° C.). The column is eluted with portions of solvents, followingprogress by examining the infra-red spectra of the products obtained byevaporating the eluates. The column is washed with the same solvent(1500 ml.) which elutes 4-chloroiodobenzene. Elution is then continued,using a 19:1 mixture of light petroleum (b.p. 40°-60° C.) and ether. Thefirst 100 ml. of eluate yields a mixed product which is discarded.Continued elution with 700 ml. of the mixed solvent then elutes theproduct (30.6 g.; I.R. spectral max 1767 cm.⁻¹), which is distilled togive ethyl2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.122°-123° C. at 23 mm. (23.1 g.).

The above procedure is repeated except that thedi-(4-chlorophenyl)iodonium chloride is replaced by a molar equivalentquantity of:

diphenyliodonium chloride,

di-(4-methoxyphenyl)iodonium bromide,

di-(4-fluorophenyl)iodonium chloride, or

di-(1-naphthyl)iodonium mixed bromide and chloride.

In the case of diphenyliodonium chloride, the desired product is elutedfrom the silica column with a 2:1 mixture of light petroleum and ether,needing a forerun of 1.3 l. and 750 ml. of solvent to elute the productethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.102°-104° C. at 23 mm. pressure (32.5 g. from 36.0 g. of ethyl2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate).

In the case of di-(4-methoxyphenyl)iodonium bromide, the vigorousreaction occurs at 170° C. and the mixture is heated at 180° C. for 10minutes. The silica column is eluted with a 19:1 mixture of lightpetroleum and ether throughout, and after a forerun of 1250 ml., afurther 1250 ml. of solvent elutes ethyl2-(4-methoxyphenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.141°-142° C. at 12 mm. pressure (5.3 g.).

In the case of di-(4-fluorophenyl)iodonium chloride, the vigorousreaction occurs at 104° C. and the mixture is heated at 100°-110° C. for1 hour. The silica column is washed with light petroleum (b.p. 40°-60°C.) then mixtures of light petroleum and ether (49:1, 600 ml.; 19:1, 300ml.), and the product is then eluted with 300 ml. of a 10:1 mixture oflight petroleum and ether to give ethyl2-(4-fluorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.92°-94° C. at 12 mm. pressure (4.6 g. from 12 g. of starting ester).

In the case of di-(1-naphthyl)iodonium mixed bromide and chloride, thevigorous reaction occurs at 130° C. and the mixture is heated at 140° C.for 1 hour. The silica column is washed with light petroleum (b.p.40°-60° C.), and the product eluted with a 19:1 mixture of lightpetroleum and ether to give ethyl2-(1-naphthyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.89°-91° C. at 0.1 mm pressure (8.5 g. from 12 g. of starting ester).

EXAMPLE 22

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) isadded dropwise at 0° C. to a stirred suspension of sodium hydride (2.0g. of a 60% emulsion in oil from which the oil has been wshed withxylene) in xylene (200 ml.). The mixture is stirred at 0° C. for 1.5hours, and di-(4-chlorophenyl)iodonium chloride (18.7 g.) is added. Thestirred suspension is heated under reflux for 1.5 hours, cooled, andfiltered. The filtrate is evaporated in vacuo and the residual oil (30.4g.) is chromatographed on a column of silica (150 g.) in light petroleum(b.p. 40°-60° C.). Elution with the same solvent (750 ml.) elutes4-chloroiodobenzene. Further elution with the solvent (1000 ml.) andwith a mixture of light petroleum and ether (19:1) (1000 ml.) elutes theoily product (14.5 g.) which is fractionally distilled to give ethyl2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (11.7g.) b.p. 122°-123° C. at 20 mm. pressure.

EXAMPLE 23

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) isadded, dropwise at 0° C. under nitrogen, to a stirred mixture of toluene(200 ml.) and sodium hydride (2.0 g. of a 60% dispersion in oil fromwhich the oil has been washed with toluene). The mixture is stirred atambient temperature for 1.5 hours, and phenyl-2-thienyliodoniumtrifluoroacetate (20.0 g.) is added. The mixture is heated under refluxwith continued stirring for 1 hour, then cooled, and filtered. Thefiltrate is evaporated in vacuo, and the residual red oil (22.2 g.) isfractionally distilled at 24 mm. pressure to give ethyl2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p. 103°-105° C.(9.4 g.).

The above process is repeated except that the phenyl-2-thienyliodoniumtrifluoroacetate is replaced by a molar equivalent of4-biphenylyl-2-thienyliodonium chloride and the residual oil ischromatographed on silica gel, washed with light petroleum (b.p. 40°-60°C.; 1.5. l.) and a 99:1 mixture of light petroleum and ether (500 ml.),and eluted with a 50:1 (1.5 l. )and a 20:1 (1.5 l.) mixture of lightpetroleum and ether. The eluate is evaporated, and the residue distilledto give ethyl2-(4-biphenylyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p.115°-116° C. at 0.1 mm. pressure (16.5 g. from 15 g. of starting ester).

The 4-biphenylyl-2-thienyliodonium chloride used as starting materialmay be obtained as follows:

A mixture of thiophene (21.9 g.) and acetic anhydride (150 ml.) is addeddropwise at -20° C. to a stirred mixture of (diacetoxyiodo)-4-biphenyl(50 g.), acetic anhydride (125 ml.) and trifluoroacetic acid (37.5 ml.).The mixture is stirred at -20° C. for 2 hours, at -10° C. for 2 hours,and at 0° C. for 18 hours. The mixture is evaporated in vacuo below 40°C., and the residue is washed in turn with water, ether, and lightpetroleum. The solid is crystallised twice from toluene, and suspendedin water (500 ml.). Ethanol (750 ml.) is addd until the solid dissolves,and the solution is poured into a solution of ammonium chloride (15.0g.) in water (50 ml.). The precipitated solid is filtered off, washedwith water, stirred with water (500 ml.) for 2 hours at ambienttemperature, then filtered off and washed with water and ether, to give4-biphenylyl-2-thienyliodonium chloride (35.1 g.), m.p. 209°-210° C.

EXAMPLE 24

Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (18.0 g.) isadded, dropwise at 0° C. under nitrogen, to a stirred mixture of lightpetroleum (b.p. 60°-80°, 300 ml.) and sodium hydride (3.0 g. of a 60%dispersion in oil from which the oil has been washed with lightpetroleum). The mixture is stirred for 10 minutes at ambienttemperature, and 4-(4-chlorophenyl)phenyl-2-thienyliodoniumtrifluoroacetate (18.3 g.) is added. The mixture is stirred until wellmixed, and is then evaporated in vacuo. The residue is heated in a bathto 110° C. at which temperature a vigorous reaction occurs. When itsubsides, toluene (400 ml.) is added and the stirred mixture is heatedunder reflux for 1 hour, cooled and filtered. The filtrate is evaporatedand the residue (41.6 g.) is chromatographed in light petroleum (b.p.60°-80° C.) on a column of silica gel (400 g.). The column is washedportionwise with a mixture of light petroleum and ether (99:1, 1.5 l.),then eluted with a (49:1) mixture (3.1). The eluate is evaporated togive a solid (23.8 g.) which is crystallised from methanol to give ethyl2-[4-(4chlorophenyl)phenoxy]-3,3,3-trifluoro-2-trifluoromethylpropionatem.p. 44°-45° C.

The 4-(4-chlorophenyl)phenyl-2-thienyliodonium trifluoroacetate used asstarting material may be obtained as follows:

Peracetic acid (40%, 13 ml.) is added dropwise to a stirred suspensionof 4-(4-chlorophenyl)iodobenzene (12.6 g.) in acetic acid (25 ml.) at30° C. during 1hour. The mixture is stirred at 30° C. for 6 hours, andat ambient temperature for 2 days, then evaporated to dryness in vacuo.The residue is washed with light petroleum, and is crystallised fromchloroform to give 4-(4-chlorophenyl)-(diacetoxyiodo)-benzene (10.7 g.)m.p. 147°-150° C.

A mixture of thiophene (8.7 g.) and acetic anhydride (60 ml.) is addedto a stirred suspension of 4-(4-chlorophenyl)-(diacetoxyiodo)benzene(21.7 g.) in a mixture of acetic anhydride (50 ml.) and trifluoroaceticacid (15 ml.) below -10° C. during 1 hour. The mixture is stirred at-10° C. for 2 hours, at ambient temperature for 18 hours and is thenfiltered. The filtrate is concentrated to small volume in vacuo, andether is added. The solid so formed is filtered off and crystallisedfrom toluene to give 4-(4-chlorophenyl)-phenyl-2-thienyliodoniumtrifluoroacetate (13.7 g.), m.p. 175°-177° C.

EXAMPLE 25

A mixture of ethyl2-(4-chlorophenoxy)-3,3,3-trifluoro2-trifluoromethylpropionate (14.6g.), 4.5 N-aqueous potassium hydroxide (19.2 ml.) and methanol (35 ml.)is stirred at ambient temperature for 21/4 hours. The resulting solutionis diluted with water and washed with ether. The aqueous phase isacidified with concentrated hydrochloric acid, and extracted with ether.The extract is washed with water, dried with sodium sulphate andevaporated. The residue is sublimed twice at 100° C. and 0.3 mm.pressure, and the sublimate is washed with light petroleum (b.p. 30°-40°C.) to give 2-(4-chloropheonxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 81°-83° C. (5.1g.). The acid may be further purified by crystallisation (prisms) fromlight petroleum (b.p. 60°-80° C.) followed by sublimation, which yieldsmaterial of m.p. 82°-83° C.

The above process is repeated except that the ethyl2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate isreplaced by ethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate(13 g.) and the residue obtained by evaporation of the ethereal extractis purified by distillation at 10⁻³ mm. pressure, crystallisation frompetrol (b.p. 30°-40° C.) at -65° C. and redistillation to give2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid, b.p. 68°-70°C, at 10⁻³ mm., m.p. 6°-8° c. (8 g.).

The above process is repeated except that the ethyl2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate isreplaced by ethyl2-(4-fluorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (8.6g.), ethyl 2-(1-naphthyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate(4.8 g.), ethyl2-(4-biphenyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (1.96 g.)or ethyl2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro2-trifluoromethylpropionate(3.35 g.) and the 19.2 ml. of 4.5N-aqueous potassium hydroxide isreplaced by an equivalent quantity (based of the amount of startingester) of 5.2N-aqueous potassium hydroxide. In the case of ethyl2(1-naphthyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, thehydrolysis is continued for 41/2 hours. In each case the sublimationstep is omitted, and the residue after evaporation of the etherealextract is crystallised from light petroleum (b.p. 60°-80° C.) to give2-(4-fluorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid,m.p. 77°-78° C. (1.5 g.),2-(1-naphthyloxy)3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p.125°-126° C. (0.46 g.),2-(4-biphenylyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid,m.p. 137°-138° C. (1.15 g.), or2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid, m.p. 159°-160° C. (1.15 g.), respectively.

EXAMPLE 26

An excess of a solution of diazomethane in ether is added to an etherealsolution of2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid(0.25 g.) at 0° C. Evaporation of the resulting solution yields methyl2(4chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (0.25 g.),b.p. (bath temperature) 140° C. at 30 mm. pressure.

The procedure is repeated using as the acid,2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid (0.10 g.) togive methyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate (0.1g) b.p. (bath temperature) 130° C. at 30 mm. pressure.

EXAMPLE 27

An excess of ice-cold aqueous ammonia (d, 0.88) is added at 0° C. to2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride(151 mg.), and the crystals which separate are collected andrecrystallised from a mixture of benzene and light petroleum (b.p.60°-80° c.) to give2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionamide (49mg.), m.p. 77°-79° C.

The acid chloride used as starting material is obtained as follows:-

A mixture of2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid (161mg.), thionyl chloride (200 mg.), dimethylformamide (20 mg.) and lightpetroleum (2 ml. b.p. 40°-60° C.) is heated under reflux for 15 minutesand the solvent evaporated. Light petroleum (5 ml. is added, and theevaporation repeated. The residue is dissolved in light petroleum, thesolution filtered and evaporated to give2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride(151 mg.) as an oil.

EXAMPLE 28

(±)-Methyl 2-hydroxy-2-trifluoromethylpropionate (25.8 g.) is addeddropwise at 0° C. under nitrogen to a stirred suspension of sodiumhydride (6.0 g. of a 60% dispersion in oil from which the oil has beenwashed with toluene) in toluene (250 ml.). The mixture is stirred atambient temperature for 30 minutes, and di-(4-chlorophenyl)iodoniumchloride (57.9 g.) is added. The stirred suspension is heated underreflux for 1 hour, cooled, and filtered. The filtrate is evaporated invacuo, and the residual oil (73.1 g.) is chromatographed on a column ofsilica gel (370 g.) in light petroleum (b.p. 40°-60° C.). The column iswashed portionwise with the solvent (2.1 l.), and with a mixture oflight petroleum and ether (19:1, 750 ml.). Further washing with themixed solvent (400 ml.) elutes impure product (2 g.) followed after afurther 600 ml. of solvent by the product (22.0 g.). The last fractionis distilled to give (±)-methyl2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionate b.p. 117°-120° C.at 12 mm. pressure (15.3 g.).

EXAMPLE 29

A mixture of (±)-methyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionate (1.41 g.), methanol (4.0 ml.), and 4.5 N-aqueouspotassium hydroxide (2.3 ml.) is stirred at ambient temperature for 10minutes. The resulting solution is diluted with water, washed withether, acidified with concentrated hydrochloric acid, and extracted withether. The extract is washed with water, dried with sodium sulphate andevaporated to a residue which is crystallised from light petroleum (b.p.60°-80° C.) to give(±)-2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p.141°-142° C. (0.7 g.).

EXAMPLE 30

(±)-Methyl 2-hydroxy-2-trifluoromethylpropionate (8.6 g.) is addeddropwise, at 0° C. under nitrogen, to a stirred suspension of sodiumhydride (2.0 g. of a 60% dispersion in oil from which the oil has beenwashed with toluene) is toluene (250 ml.). The mixture is stirred atambient temperature for 15 minutes, and4-(4-chlorophenyl)phenyl-2-thienyliodonium trifluoroacetate (25.5 g.) isadded. The mixture is stirred and heated under reflux for 1 hour, thencooled and filtered. The filtrate is evaporated, and the residue isdigested with ether. The ether is evaporated to give (±)-methyl2-[4-(4chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionate as asolid.

EXAMPLE 31

A mixture of (±)-methyl2-[4-(4-chlorophenyl)phenoxy]3,3,3-trifluoro-2-methylpropionate (20 g.),methanol (120 ml.) and 5.2 N-aqueous potassium hydroxide (13 ml.) isstirred at ambient temperature for 18 hours. Most of the methanol isevaporated in vacuo, and water is added. The mixture is washed withlight petroleum, and concentrated hydrochloric acid added to the aqueousphase. The mixture is extracted with ether, and the extract is driedwith sodium sulphate, treated with carbon and evaporated. The residue iscrystallised from toluene to give(±)-2[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid,m.p. 198°-199° C. (8.35 g.).

EXAMPLE 32

A solution of(±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid(3.0 g.) in ether (100 ml.) is treated with an excess of etherealdiazomethane at 0° C. The solvent is evaporated and the residuerecrystallised from methanol to give(±)-methyl-2-]4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionate,m.p. 87°-88° C.

EXAMPLE 33

Ice-cold aqueous ammonia (5 ml., d, 0.91) is added to(±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methyl propionylchloride (401 mg.) with stirring. The solid is filtered off, washed withwater, dried, and is crystallised from a mixture of benzene and lightpetroleum (b.p. 60°-80° C.) to give(±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionamide,m.p. 141°-142° C. (342 mg.).

The acid chloride used as starting material may be obtained as follows:

A solution of(±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid(414 mg.), thionyl chloride (1.0 g.) and dimethylformamide (0.05 g.) inbenzene (10 ml.) is heated under reflux for 1 hour. The solvent isevaporated in vacuo, and light petroleum (10 ml., b.p. 60°-80° C.) isadded, and the mixture is re-evaporated. A further 10 ml. of lightpetroleum are added, and the mixture re-evaporated. The residue isdissolved in light petroleum, and the solution is filtered andevaporated to give(±)-2-[4-(4-chlorophenyl)-phenoxy]-3,3,3-trifluoro-2-methylpropionylchloride (401 mg.).

EXAMPLE 34

A mixture of (±)-methyl 2-hydroxy-3,3,3-trifluoropropionate (7.9 g.) intoluene (150 ml.) is added, dropwise at 0° C. under nitrogen, to astirred mixture of toluene (200 ml.) and sodium hydride (2.0 g. of a 60%dispersion in oil from which the oil has been washed with toluene). Themixture is stirred at ambient temperature for 1 hour,4-(4-chlorophenyl)-phenyl-2-thienyliodonium trifluoroacetate (25.5 g.)is added, and the mixture is heated under reflux for 1 hour withcontinued stirring, then cooled and filtered from unreacted iodoniumsalt. The residue obtained by evaporating the filtrate is treated withether, the mixture is filtered and the filtrate is evaporated. Theresidue is triturated with three 100 ml. portions of light petroleum andthe extracts set aside. The residue is extracted with ether, and thesolution filtered. The filtrate is evaporated, and the residuecrystallised from ethanol. The mother liquors are evaporated, and theresidue is chromatographed in light petroleum (b.p. 60°-80° C.) on acolumn of silica gel (150 g.). The column is eluted, portionwise, with amixture of light petroleum and ether (100:1; 1250 ml.) and then with a50:1 mixture (1300 ml.) and a 25:1 mixture (250 ml.). The last fractionis evaporated, and the residue combined with a solid which separatesfrom the in initial light petroleum extracts. The combined material iscrystallised from methanol and from light petroleum (b.p. 80°-100° C.)to give (±)-methyl2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoropropionate, m.p. 104°-105°C. (1.8 g.).

The (±)-methyl 2-hydroxy-3,3,3-trifluoropropionate used as startingmaterial may be obtained as follows:

A mixture of (±)-2-hydroxy-3,3,3-trifluoropropionic acid (7.8 g.),methanol (10 ml.) and concentrated sulphuric acid (0.5 ml.) is heatedunder reflux for 2 days. The cooled solution is poured into water (100ml.), the mixture is saturated with sodium sulphate, and is extractedthree times with ether. The extract is dried with sodium sulphate andevaporated. The residual oil (8.6 g.) is fractionally distilled to give(±)-methyl 2-hydroxy-3,3,3-trifluoropropionate b.p. 60°-64° C. at 12 mm.pressure, m.p. 50°-53° C. (3.9 g.).

EXAMPLE 35

A solution of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionicacid (2.06 g.) in dimethylformamide (10 ml.) is added dropwise at 0° C.under argon to a stirred suspension of sodium hydride (216 mg. of a 60%dispersion in oil from which the oil has been washed with lightpetroleum) in dimethylformamide (15 ml.). The mixture is heated at 100°C. for 18 hours, cooled, and evaporated in vacuo. The residue is mixedwith water and the solid obtained (1.8 g.) is washed with water anddried, then chromatographed in toluene on a column of silica (60 g.).The column is washed with toluene (900 ml.) until no more material iseluted, and then with ether. The ether is evaporated and the solid (0.4g.) is crystallised from light petroleum to give(±)-N,N-dimethyl-2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoropropionamide,m.p. 103°-107° C. (212 mg.).

EXAMPLE 36

A mixture of(±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid (0.36 g.), N aqueous sodium hydroxide (1.0 ml.) and water (3.0 ml.)is stirred until no more of the acid dissolves. The mixture is filtered,the filtrate is washed with ether and evaporated in vacuo. The residueis crystallised from a mixture of ethyl acetate and light petroleum(b.p. 60°-80° C.) to give (±)-sodium2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (0.3g.) m.p. 271°-272° C. (decomposition).

EXAMPLE 37

A solution of(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride(1.3 g.) in ether (10 ml.) is added to a mixture of ammonia (d, 0.90; 10ml.) and water (100 ml.). The mixture is shaken, and the ether isevaporated. The solid is filtered off and crystallised from lightpetroleum (b.p. 100°-120° C.) to give(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionamide (0.76 g.)m.p. 111°-112° C.

The (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chlorideused as starting material is obtained as follows:

A solution of(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.0g.), thionyl chloride (7.5 ml.) and dimethylformamide (0.2 g.) inbenzene (50 ml.) is heated under reflux for 10 minutes. The mixture isevaporated, benzene (20 ml.) is added and the evaporation repeatedtwice. Light petroleum (b.p. 40°-60° C., 150 ml.) and carton are addedto the residue, and the solution is filtered and evaporated to give(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride(5.35 g.) m.p. 39°-43° C.

EXAMPLE 38

A solution of(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride(3.0 g.) in ether (20 ml.) is added dropwise at ambient temperature to astirred solution of 2-diethylaminoethanol (3.0 ml.) in ether (100 ml.).The mixture is stored for 18 hours, filtered, and the solid is washedwith ether. The filtrate and washings are evaporated to an oil (3.5 g.),which is dissolved in ether and run through a column of silica gel madeup in ether. The column is eluted with 200 ml. of ether, and the eluateevaporated to give 2.4 g. of an oil which is similarly passed through acolumn of alumina (Neutral, Grade I, 30 g.). Elution with ether yields(±)-2-diethylaminoethyl2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.05 g.) as anoil.

EXAMPLE 39

A solution of(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride(4.3 g.) in benzene (20 ml.) is added, dropwise below 10° C., to astirred solution of 3-pyridylmethanol (1.20 g.) and pyridine (1.10 g.)in benzene (20 ml.) and light petroleum (5 ml. b.p. 40°-60° C.). Themixture is stirred at 5° C. for 1 hour, and at ambient temperature for18 hours. The mixture is filtered. The filtrate is diluted with ether,washed with water, aqueous sodium carbonate and water, dried with sodiumsulphate, and evaporated to give an oil (4.1 g.). The oil is dissolvedin a mixture of ethyl acetate, ethanol, and triethylamine (200:1:1) andis chromatographed on a column of silica gel (210 g.) made up in thesame solvent. The column is eluted portionwise with the solvent. Thefirst 350 ml. elutes an impurity (0.1 g.). The following 420 ml. ofeluant is evaporated to give(±)-3-pyridylmethyl-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate(3.9 g.) as a syrup.

EXAMPLE 40

A solution of(±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride(3.0 g.) in tetrahydrofuran (70 ml.) is added, dropwise at 0° C., to astirred solution of 4-hydroxy-N,N-dimethylbutyramide (1.20 g.) andtriethylamine (2.1 g.) in tetrahydrofuran (35 ml.). The mixture isstored for two days. The solid is filtered off and washed with ether,and the filtrate and washings are evaporated. The residue is dissolvedin ether and the solution is washed with water, 0.4 N aqueous sodiumhydroxide, and water, dried with magnesium sulphate, and evaporated. Theresidue is crystallised from a mixture of light petroleum (b.p. 40°-60°C.) and ether to give (±)-3-dimethylcarbamoylpropyl2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.3 g.) m.p.42°-43° C.

EXAMPLE 41

A solution of N,N-dimethylaniline (0.90 g.) in tetrahydrofuran (10 ml.)is added dropwise, below 5° C., to a stirred solution of (±)-2l-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (2.2 g.)and 1,3-dihydroxypropane (0.25 g.) in tetrahydrofuran (10 ml.). Themixture is stirred at ambient temperature for 18 hours, and then afurther 0.3 g. of the acid chloride and 0.12 g. of N,N-dimethylanilineare added. The mixture is stirred and heated under reflux for 2 hours,and then evaporated in vacuo. The residue is partitioned between etherand water, and the ethereal layer is washed with 3N hydrochloric acid,water 0.4 N aqueous sodium hydroxide, and water, dried with sodiumsulphate, and evaporated. The residual oil (1.6 g.) is dissolved inether and the solution applied to a column of silica gel. (20 g.). Thecolumn is eluted with ether (10 ml., which is discarded and then 25ml.), and the eluate evaporated to give (±)-trimethylene bis[2-(2naphthylmethoxy)3,3,3-trifluoro-2-methylpropionate ] (0.60 g.), as asyrup.

EXAMPLE 42

A solution of (-) ephedrine (4.15 g.) in ether (100 ml.) is added to asolution of(±)-2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid (9.00 g.) in ether (100 ml.). After 18 hours the crystalline saltis filtered off and washed with ether. The filtrate and washings areretained (A). The crystalline salt (4.7 g., m.p. 161°-167° C., [α]_(D)²⁵ -13°; c, 2.3 in methanol) thus obtained is crystallised three timesfrom toluene to give salt (B), and combined mother-liquors (C). Salt (B)(2.5 g., m.p. 169°-170° C. [α]_(D) ²⁵ -11°; c, 1.8 in methanol) isshaken for 2 minutes with ether (200 ml.) and 2N aqueous hydrochloricacid (150 ml.). The ethereal layer is separated, and is washed withwater, dried with sodium sulphate, and evaporated to give the free acid(1.3 g., m.p. 125°-127° C. [α]_(D) ²⁵ + 2.3°; c, 2.2 in methanol), whichis recrystallised twice from light petroleum (b.p. 80°-100° C.) to give(±)-2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid as prisms (0.90 g.), m.p. 124°-125° C., [α]_(D) ²⁵ + 1.7°; c, 1.7in methanol.

The above mother-liquors (A and C) are combined and evaporated. Theresidual salts are converted into the corresponding free acid (4.4 g.,[α]_(D) ²⁵ -0.4°; c 1.9 in methanol), as described for salt (B). Racemicacid (5.70 g.) is added (total 10.10 g.), and this material in ether(100 ml.) is treated with a solution of (±)-ephedrine (4.65 g.) in ether(100 ml.). After three hours, the separated salt is collected and iscrystallised three times from toluene to give a salt (4.6 g., m.p.169°-171° C., [α]_(D) ²⁵ + 11°; c, 1.9 in methanol). This salt isconverted into the free acid (3.1 g., m.p. 124°-125° C., [α]_(D) ²⁵ -1.7°; c, 2.1 in methanol) as described for salt (B), and the acid iscrystallised once from cyclohexane and once from light petroleum (b.p.80°-100° C.) to give(-)-2-[4-(4-chlorophenyl)-benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid as prisms (1.7 g.), m.p. 124°-125° C., [α]_(D) ²⁵ - 1.85°; c, 1.8in methanol.

EXAMPLE 43

The process of Example 16 is repeated except that he4-(4-chlorophenyl)benzyl chloride is replaced by a molar equivalentquantity of 2-chloromethyl-6-methoxynaphthalene to give (±)-methyl2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate as anoil.

The 2-chloromethyl-6-methoxynaphthalene used as starting material isobtained from methyl 6-methoxy-2-naphthoate by reaction with sodiumdihydro-bis-(2-methoxyethoxy)aluminate to give2-hydroxymethyl-6-methoxynaphthalene, m.p. 118°-120° C. and reactionwith thionyl chloride to give 2-chloromethyl-6-methoxynaphthalene, m.p.63°-65° C. by the general procedure described in Example 4 for thepreparation of 2-chloromethyl-6-chloronaphthalene.

EXAMPLE 44

The process of Example 17 is repeated using (±)-methyl2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate,obtained as an oil in Example 43, as starting material except that thepotassium hydroxide is replaced by 4.4 N aqueous sodium hydroxide andthe reaction is carried out for 21/2 hours to give(±)-2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionicacid, m.p. 117°-119° C. (from light petroleum b.p. 60°-80° C.).

EXAMPLE 45

A solution of(±)-2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionicacid (1.0 g.) in ether is treated with diazomethane by the processdescribed in Example 18 to give (±)-methyl2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (0.8g.) m.p. 60°-62° C. (from methanol at -50° C.).

EXAMPLE 46

The process described in Example 30 is repeated except that the4-(4-chlorophenyl)phenyl-2-thienyliodonium trifluoroacetate is replacedby a molar equivalent quantity of 4-phenoxyphenyl-2-thienyliodoniumchloride. The product is obtained as an oil which is dissolved in lightpetroleum (b.p. 60°-80° C.) and applied to a column of silica gel (500g.) made up in the same solvent. The column is washed with lightpetroleum (750 ml.) and mixtures of light petroleum and ether (100:1,500 ml; 50:1, 2750 ml.) and then eluted with a 10:1 mixture of lightpetroleum and ether (1000 ml.). The eluate is evaporated and the residuedistilled to give (±)-methyl2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionate (18.1 g.), b.p.154°-160° C. at 0.05 mm. pressure.

EXAMPLE 47

A mixture of (±) methyl2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionate (10.2 g.),obtained as in Example 46, methanol (50 ml.) and 4.4 N aqueous sodiumhydroxide (7.0 ml.) is stirred at ambient temperature for 21/2 hours.The hydrolysis product is then isolated as described in Example 31 togive (±)-2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionic acid(6.4 g.), m.p. 111°-112° C. (from cyclohexane).

EXAMPLE 48

A solution of (±)-2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionicacid (6.4 g.) in ether is treated with an excess of etherealdiazomethane at 0° C. The solution is evaporated and the residuedistilled to give (±)-methyl2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionate (3.3 g.), b.p.187° C. at 0.1 mm. pressure.

EXAMPLE 49

2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid(200 g.) is thoroughly mixed with lactose (400 g.) and 10% w/v aqueousgelatin solution (9 g.). The mixture is granulated and the granulesmixed with maize starch (35 g.) followed by magnesium stearate (6 g.).The mixture is then compressed into tablets containing 50, 100 or 250mg. of active ingredient.

The 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionicacid may be replaced by a salt thereof or any compound of formula Idescribed in any of Examples 1-48 which is a solid at room temperature.

EXAMPLE 50

Methyl 2-[4-(4-chlorphenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionateis filled into soft gelatin capsules each containing either 250 mg. or500 mg. of active ingredient.

The active ingredient may be replaced by any compound of formula Idescribed in any of Examples 1-48 and, if desired, the active ingredientmay include a diluent.

What we claim is:
 1. A fluorinated compound of the formula:-##STR9##wherein Ar is a phenyl or naphthyl radical which, may optionallybear as substituent a halogen atom, an alkyl radical of 1-4 carbon atomsor an alkoxy radical of 1-4 carbon atoms, or a phenyl or phenoxy radicalwhich may itself bear as substituent a halogen atom, an alkyl radical or1-4 carbon atoms or an alkoxy radical of 1-4 carbon atoms; X is --CH₂--; R¹ is a hydroxy radical or an alkoxy radical of 1-6 carbon atoms;and R² is a hydrogen atom, a methyl radical or a trifluoromethylradical; or, for a compound wherein R¹ is a hydroxy radical, apharmaceutically acceptable base addition salt thereof.
 2. A compound asclaimed in claim 1 wherein Ar is a phenyl or naphthyl radical which mayoptionally bear as substituent a fluorine, chlorine, bromine or iodineatom, or a methyl or methoxy radical or a phenyl or phenoxy radicaloptionally bearing a fluorine, chlorine, bromine or iodine atom or amethyl or methoxy radical; R¹ is a hydroxy radical or an alkoxy radicalof 1-6 carbon atoms and R² is a hydrogen atom, a methyl radical ortrifluoromethyl radical.
 3. A pharmaceutically acceptable base additionsalt as claimed in claim 1 which is an alkali metal or alkaline earthmetal salt, or an aluminum salt or a salt with an organic base.
 4. Acompound as claimed in claim 1 wherein R² is other than atrifluoromethyl radical which is in an optically active form.
 5. Acompound as claimed in claim 1 selected from the group consisting of2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acidand the pharmaceutically acceptable base addition salts thereof.
 6. Acompound as claimed in claim 1 selected from the group consisting of2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acidand the pharmaceutically acceptable base addition salts thereof.
 7. Acompound as claimed in claim 1 selected from the group consisting of2-(2-naphthylmethoxy)-3,3,3trifluoro-2-methylpropionic acid and thepharmaceutically acceptable base addition salts thereof.
 8. A compoundas claimed in claim 1 selected from the group consisting of2-(1-naphtylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid and thepharmaceutically acceptable base addition salts thereof.